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Genetics of Neonatal Hyperinsulinism

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Genetics of Neonatal Hyperinsulinism Arch Dis Child Fetal Neonatal Ed 2000;82:F79–F86 F79 Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.82.2.F79 on 1 March 2000. Downloaded from HYPERINSULINISM Genetics of neonatal hyperinsulinism Benjamin Glaser, Paul Thornton, Timo Otonkoski, Claudine Junien Abstract Netherlands.2 In areas of high consanguinity, Congenital hyperinsulinism (HI) is a the incidence can be as high as one in 3000.13 clinically and genetically heterogeneous The clinical heterogeneity includes a highly entity. The clinical heterogeneity is mani- variable age of onset, severity, and responsive- fested by severity ranging from extremely ness to medical treatment. The pathological severe, life threatening disease to very findings are also variable, and two distinct his- mild clinical symptoms, which may even topathological forms have been described. be diYcult to identify. Furthermore, clini- Most cases show diVuse involvement of â cells cal responsiveness to medical and surgical throughout the pancreas (diVuse HI), whereas management is extremely variable. Re- some have focal adenomatous hyperplasia cent discoveries have begun to clarify the (focal HI), in which a distinct region of the Department of molecular aetiology of this disease and pancreas appears to be involved, the remainder Endocrinology and thus the mechanisms responsible for this of the pancreas being histologically and func- Metabolism, The clinical heterogeneity are becoming more tionally normal. Genetic heterogeneity has also Hebrew University, been described. Mutations in four diVerent Hadassah Medical clear. Mutations in 4 diVerent genes have School, Jerusalem, been identified in patients with this clini- genes have been detected in patients with HI, http://fn.bmj.com/ 91120, Israel cal syndrome. Most cases are caused by and both autosomal recessive and dominant B Glaser mutations in either of the 2 subunits of the inheritance has been demonstrated. However, + in many cases the genetic aetiology is still not Division of â cell ATP sensitive K channel (KATP), Endocrinology, whereas others are caused by mutations in known. In this review, we will attempt to Department of the â cell enzymes glucokinase and gluta- provide an update for each of the known Paediatrics, University of Pennsylvania School mate dehydrogenase. However, for as subclassifications of HI, while emphasising of Medicine, many as 50% of the cases, no genetic aeti- those areas where research is still needed. on October 1, 2021 by guest. Protected copyright. Philadelphia, PA ology has yet been determined. The study 19104, USA of the genetics of this disease has provided P Thornton Control of insulin secretion important new information about â cell To understand the pathophysiology of the vari- Transplantation physiology. Although the clinical ramifi- ous forms of HI, one must understand the Laboratory, Haartman cations of these findings are still limited, Institute, University of mechanisms responsible for glucose homeosta- Helsinki, Helsinki FIN in some situations genetic studies might sis. Under normal conditions, the circulating 00014, Finland greatly aid in patient management. glucose concentration is regulated, primarily T Otonkoski ( 2000;82:F79–F86) Arch Dis Child Fetal Neonatal Ed by insulin, to within a very tight range. INSERM Unité 383, Keywords: hypoglycaemia; sulphonylurea receptor; Unregulated release of insulin will result in Génétique, hypoglycaemia with resultant neuroglycopenia Chromosome et ATP sensitive potassium channel; hyperinsulinism Cancer, Hopital des and, if uncontrolled, irreversible brain damage. Enfants Malades, The major factors that control glucose 75743 Paris, France Congenital hyperinsulinism (HI) is a heteroge- stimulated insulin secretion are described in fig Claudine Junien neous entity, the genetics of which have only 1. Although this figure gives a highly simplified Correspondence to: recently begun to be elucidated. The incidence description of the regulation of insulin secre- Dr B Glaser, Division of Endocrinology and of HI in the general population ranges from tion and fails to consider multiple other Metabolism, Hadassah one in 27 000 in the Irish population (P pathways that modulate the response to University Hospital, PO Box 12000, Jerusalem, Israel Thornton, unpublished observations) to one in glucose and to other stimuli, it is suYcient for email: [email protected] 40 000 in Finland,1 and one in 50 000 in the the purpose of the discussion here. F80 Glaser, Thornton, Otonkoski, Junien Arch Dis Child Fetal Neonatal Ed: first published as 10.1136/fn.82.2.F79 on 1 March 2000. Downloaded from The normal, resting â cell membrane is tion and unregulated insulin secretion. In most maintained in a hyperpolarised state by the cases, insulin secretion will not respond to dia- Na+–K+ ATPase pump and open, ATP sensitive zoxide or to tolbutamide because a functional potassium channels (KATP). These channels channel is required for these drugs to exert sense the metabolic state of the cell. When their eVect. However, some KATP mutations plasma glucose increases, it enters the â cell might cause lack of function in the natural through a specific membrane-bound glucose state, yet retain the ability to respond to phar- transporter—GLUT-2. It is then phosphor- macological intervention. ylated by the enzyme glucokinase and metabo- In contrast, mutations that increase nutrient lised, resulting ultimately in the phosphoryla- metabolism and thus increase the ATP/ADP tion of ADP to ATP, thereby increasing the ratio will result in insulin secretion that is sup- pressible with diazoxide. As described below, ATP/ADP ratio. This causes the KATP channels to close, which results in depolarisation of the mutations at both of these sites have been cell membrane, opening of voltage dependent found in patients with HI. Theoretically, muta- Ca2+ channels, and a rise in the free intracellu- tions in genes responsible for functions down- 2+ lar Ca concentration. This, in turn, activates stream from the KATP channel, such as the volt- 2+ the insulin secretory mechanisms. Glucokinase age gated Ca channels or genes involved in is the rate limiting step in the metabolism of the mobilisation of secretory granules, could glucose and is thus a key step in the regulation also cause unregulated insulin secretion, al- of the secretion of insulin. The ATP/ADP ratio though no such mutations have yet been iden- can be increased by metabolism of substrates tified. other than glucose, such as amino acids. Activating mutations of glutamate dehydroge- Mutations in the â cell KATP channel nase (GDH) cause unregulated insulin secre- The first evidence that HI is a genetic disease came with the identification of rare families tion, possibly by increasing the flux of sub- 6–14 strates into the citric acid cycle, thus increasing with aVected siblings. More concrete evi- the ATP/ADP ratio. dence for autosomal recessive inheritance came from statistical analysis of relatively large The KATP channel can be regulated by drugs, 15 16 the most common of which are the antidiabetic groups of patients and their families. Link- age studies carried out in a subgroup of sulfonylureas (tolbutamide, glibenclamide, gli- families selected specifically for evidence of pizide, and others), which cause closure of the recessive inheritance (at least two aVected sib- channel, membrane depolarisation, and insulin lings with unaVected parents) showed linkage secretion. Diazoxide has the opposite eVect, to chromosome 11p15.1, which was subse- increasing the channel’s mean open probabil- quently confirmed.17 18 ity, thus inhibiting insulin secretion, and is Soon after the linkage was established, the â commonly used in states of unregulated insulin cell sulfonylurea receptor gene (SUR1) was secretion, particularly insulinomas and some cloned.19 The gene was located within the cru- cases of HI. A natural ligand for the K chan- ATP cial region for the HI gene, as defined by link- nel has been described recently (endosul- age analysis, and mutations were identified in phine), but its physiological role in the regula- 20 45 nine families with HI. Thus, the first HI asso- tion of insulin secretion is still unknown. ciated gene was discovered. Soon thereafter, Mutations in several diVerent genes might be + the gene encoding the inward rectifying K http://fn.bmj.com/ predicted to cause a similar phenotype: inap- channel (KIR6.2) was cloned and it was propriate insulin secretion and hypoglycaemia. discovered that together with SUR1 the Mutations that decrease or destroy KATP chan- product of this gene formed the â cell KATP nel activity will result in continuous depolarisa- 21 channel. Dunne et al proved the association between SUR1 mutations, K channel func- + ATP K tion, and HI by demonstrating a lack of K Sulfonylureas Ca++ ATP SUR-1 channel function in â cells obtained at the time on October 1, 2021 by guest. Protected copyright. of pancreatectomy from a patient known to be Diazoxide homozygous for an SUR1 mutation.22 The Depolarisation KIR6.2 gene is located adjacent to the SUR1 Kir 6.2 gene on chromosome 11p and, based on the ATP/ADP linkage data, it too is a candidate gene for HI ratio 23 Ca++ associated mutations. 24–26 α ketoglutarate To date, three KIR6.2 mutations and K+ Glucose-6-P + NH3 more than 40 SUR1 mutations have been reported.1 20 26–30 SUR1 mutations are spread Glucokinase GDH throughout the coding region of the gene (fig GLUT-2 Glucose 2), although there is an apparent clustering of Glucose Glutamate mutations in the second nucleotide
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